RA is a chronic inflammatory disease that often leads to joint damage, deformity, and dysfunction. The treatment of this disease has been hampered by an incomplete understanding of its pathogenesis and the absence of identifiable etiologic factors. The etiology of RA has long been suspected to be triggered by infection with bacteria, especially mycoplasma. One approach to investigating the possible role of bacterial infection in RA is empiric treatment with antibiotics. Recent studies of patients with RA of relatively long duration suggest that oral minocycline therapy modestly improves the signs and symptoms of arthritis. Minocycline, while an effective broad spectrum anti-microbial agent, can also suppress collagenase, a degradative enzyme prominent in the pathogenesis of joint destruction. Two important questions remain concerning this approach: 1-Can the clinical efficacy of minocycline in RA be improved by intensifying the antibiotic regimen and/or selectively targeting early disease? and 2-Does this class of antibiotics ameliorate joint disease in RA by suppressing the activity of collagenase and/or other related metalloenzymes? To address these issues, we propose to conduct a double-blind, placebo-controlled pilot trial of intravenous (i.v.) doxycycline therapy for RA. Sixty patients with severe RA of less than 5 years duration will be allocated into three treatment groups: I-i.v. doxycycline; II-oral azithromycin; and III-placebo. The study drug will be administered daily for 21 days and then weekly for 8 weeks by patient's at their home under the close supervision of a home care group. Outcomes will be evaluated using the American College of Rheumatology Core Disease Measures. The effects of doxycycline on collagenase activity will be examined by measuring urinary excretion of collagen cross-links. To ensure patient safety, an independent team will closely monitor for treatment side effects. These studies will provide insights into the feasibility, safety, and potential clinical efficacy of i.v. doxycycline therapy in RA and the possible effects of this agent on collagenase activity.